The Project leader's and others studies in mouse models of cancer together with a growing body of clinical studies has led to a consensus that tumors associated macrophages (TAMs) play a major role in promoting malignancy in a wide variety of cancers. During the last granting period we have established a number of functions performed by macrophages that promote tumor progression and metastasis. These are through inflammation, matrix remodeling, tumor cell invasion, intravasation, angiogenesis and extravasation. In particular, we showed that macrophages were dramatically recruited to benign lesions and thereafter control the angiogenic switch that is required for the malignant transition. In addition, together with other members of the PPG, we showed that macrophages and tumor cells are in an obligate paracrine relationship that results in tumor migration, invasion and intravasation. We have also identified a unique population of macrophages that are required for seeding and persistent growth of metastases. Importantly we demonstrated that ablation of this population resulted in an inhibition of growth of established metastatic lesions. It is the aim of the current proposal to test out the requirement for both well-established and the newly identified pathways that we have defined in macrophage sub-populations, as well as unique mouse models developed during the last granting period, to identify the mechanistic basis of the macrophage-induced traits that lead to enhanced malignancy. The specific aims are: 1. To provide the mechanistic basis for the functions of macrophage sub-populations in the tumor microenvironment 2. Define the molecular basis of macrophage regulation of angiogenesis. 3. Identify macrophage mediated mechanisms that promote metastatic seeding and persistent growth. Breast cancer is one of the most common causes of cancer death in women throughout the world. This is usually caused by metastatic disease. Our basic biology research using mouse models of cancer implicate TAMs as playing a major role in promoting the progression and metastasis of mammary cancer. Thus identifying the molecular basis for the macrophage actions proposed in this application will allow novel therapeutics targeted to these cells. Such therapeutics have an advantage over conventional ones aimed at tumor cells since these support cells do not exhibit the genetic instability of tumor cells and thus they are less likely to develop resistance.